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Differential response of glioblastomas to microtubule targeting agents

胶质母细胞瘤对微管靶向剂的差异反应

基本信息

批准号：
10434745
负责人：
Nephi Stella
金额：
$ 35.38万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-02 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434745
关键词：
Address Apoptosis Behavior Binding Biological Assay Biological Models Blood - brain barrier anatomy Brain Cancer cell line Carbazoles Cell Culture Techniques Cell Cycle Cell Survival Cell division Cells Chromosomal Instability Colchicine Collaborations Coupled DNA Damage Data Development Diagnosis Exhibits Foundations Genetic Glioblastoma Goals Grant Growth Hematologic Neoplasms Image Laboratories Link Malignant - descriptor Measures Microscopy Microtubules Mitosis Modeling Molecular Mus Non-Malignant Oncogenic Patients Penetrance Pharmacology Platelet-Derived Growth Factor Property Radiation therapy Radiation-Sensitizing Agents Radiosensitization Reporting Research Project Grants Series Site Solid TP53 gene Testing Therapeutic Time Treatment Efficacy Tubulin Work Xenograft procedure base cancer cell cancer type cell motility experimental study genetic approach in vivo in vivo Model innovative technologies insight learning algorithm live cell imaging live cell microscopy migration mouse model novel novel therapeutics pre-clinical response side effect standard care standard of care targeted agent temozolomide treatment response tumor tumorigenesis

项目摘要

Microtubule targeting agents (MTAs) are commonly prescribed to treat many types of cancers; yet their use for the treatment of glioblastomas (GBM) is limited by their poor brain penetrance. We developed a new series of MTAs (ST-compounds) that destabilize microtubules (MT) and kill GBM through a novel mechanism of action (MOA). Our recent results show that ST-compounds pass the blood brain barrier (BBB) and exhibits in vivo therapeutic efficacy in a preclinical mouse model of GBM. This new R01 uses complementary expertise and approaches to study how the novel MOA of ST- compounds differs from known MTAs and its therapeutic efficacy in several preclinical mouse model of GBM. Specifically, it leverages several innovative technologies, including live-cell imaging and artificial learning algorithms, to better understand why GBM are particularly sensitive to the antitumor activity of ST-compounds. Experiments will be performed on patient-derived GBM (PD-GBM) in culture and include measure of real-time changes in GBM cell migration, cell division and cell cycle fate as fundamental readouts of tumorigenesis. In vivo experiments will be done on both genetic orthotopic mouse models of GBM and orthotopic mouse model of PD-GBM. Our aims are: 1: Differential impact of MTAs on the migration and mitosis of GBM in culture. 2: Differential impact of MTAs on the viability and fate of GBM in culture. 3: Therapeutic efficacy and mechanism of ST-401 in GBM models in vivo. Our immediate goal is to increase our understanding of the precise MOA by which MTAs regulate GBM tumorigenesis and how this interacts with standard care treatments. This work will help set a solid foundation for the development of a new class of MTAs for the safe treatment of patients diagnosed with GBM.

微管靶向剂（MTA）通常用于治疗多种类型的癌症；但它们的用途胶质母细胞瘤（GBM）的治疗因其脑外显性差而受到限制。我们开发了一个新系列 MTA（ST 化合物）通过新颖的作用机制破坏微管 (MT) 并杀死 GBM （农业部）。我们最近的结果表明 ST 化合物可以通过血脑屏障 (BBB) 并在体内表现出 GBM 临床前小鼠模型的治疗效果。这款新的 R01 使用互补的专业知识和方法来研究 ST-的新颖 MOA 如何化合物与已知的 MTA 及其在几种 GBM 临床前小鼠模型中的治疗效果不同。具体来说，它利用了多种创新技术，包括活细胞成像和人工学习算法，以更好地理解为什么 GBM 对 ST 化合物的抗肿瘤活性特别敏感。实验将在培养的患者来源 GBM (PD-GBM) 上进行，包括实时测量 GBM 细胞迁移、细胞分裂和细胞周期命运的变化作为肿瘤发生的基本读数。在体内实验将在GBM遗传原位小鼠模型和原位小鼠模型上进行 PD-GBM。我们的目标是：图 1：MTA 对培养物中 GBM 迁移和有丝分裂的不同影响。图 2：MTA 对培养中 GBM 的生存能力和命运的不同影响。图3：ST-401在体内GBM模型中的治疗功效和机制。我们的近期目标是加深对 MTA 监管 GBM 的精确 MOA 的理解肿瘤发生及其与标准护理治疗的相互作用。这项工作将有助于奠定坚实的基础开发一类新的 MTA，用于安全治疗诊断为 GBM 的患者。